PUF60

protein-coding

poly(U) binding splicing factor 60, the group of RNA binding motif containing|Spliceosomal A complex

Gene summary

This gene encodes a nucleic acid-binding protein that plays a role in a variety of nuclear processes, including pre-mRNA splicing and transcriptional regulation. The encoded protein forms a complex with the far upstream DNA element (FUSE) and FUSE-binding protein at the myelocytomatosis oncogene (MYC) promoter. This complex represses MYC transcription through the core-TFIIH basal transcription factor. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Aug 2012]

MANE transcript

NM_078480.3

Inheritance

ClinVar variants

P:124U:126B:58

Top phenotype

Verheij syndrome

gnomAD constraint

pLI —, LoF o/e 0.08

Max pathogenic AF

—

Genomic locus

chr8:143,816,344-143,830,709

External References & Databases

Ensembl (ENSG00000179950)

Transcript & Mutation Effects

hg38 • Region Span ~14.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

8q24.3 microdeletion syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014263

Submitter: Labcorp Genetics (formerly Invitae)

8q24.3 microdeletion syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014263

Submitter: G2P

8q24.3 microdeletion syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014263

Submitter: PanelApp Australia

syndromic intellectual disabilityDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: ClinGen

Deletions of chromosome 8q24.3 were first reported in relation to Verheij syndrome in 2009 (Verheij et al., 2009; PMID: 19464398). Verheij syndrome is associated with developmental and intellectual impairments, short stature, skeletal abnormalities, feeding issues, joint laxity, renal and cardiac anomalies, coloboma, and facial dysmorphisms. A subsequent publication reported on additional probands with 8q24.3 deletions, further characterized the gene content in the region, and suggested, via zebrafish models, that the genes *PUF60* (encoding a component of the spliceosome that plays a role in RNA processing) and *SCRIB* contribute to Verheij syndrome phenotypes (Dauber et al., 2013; PMID: 24140112). In that publication, a missense *PUF60* variant shown to cause loss of function via functional studies was reported in a proband with similar clinical features (Dauber et al., 2013; PMID: 24140112). Since that time, additional publications have described individuals with variants in the *PUF60* gene. Clinical features in affected individuals with *PUF60* sequence variants are similar to those of individuals with Verheij syndrome and 8q24.3 deletions. However, the expert panel elected to curate *PUF60* for syndromic intellectual disability given the potential that *SCRIB* or other genes in the region may contribute to Verheij syndrome. At least 29 probands with *PUF60* variants have been reported in the literature. At least 19 unique nonsense, canonical splice-site, and frameshift variants have been reported in 20 probands (PMIDs: 27479843, 27804958, 28074499, 28327570, 28990276, 30078240, 30352594, 33418956) and 7 unique missense variants have been reported in 9 probands (PMIDs: 24140112, 27804958, 28074499, 28327570, 28471317, 29300383, 30569551). Missense variants cluster in the RNA recognition motifs (PMID: 30352594). The mechanism of pathogenicity is loss of function. Variants are de novo in all probands. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease association is also supported by experimental evidence including a zebrafish model (PMID: 24140112), rescue in zebrafish (PMID: 24140112), functional alteration in non-patient cells (PMID: 24140112), and rescue in cell culture (PMID: 24140112). In summary, *PUF60* is definitively associated with autosomal dominant syndromic intellectual disability. This classification was approved by the Intellectual Disability and Autism Gene Curation Expert Panel on 12/15/2021 (SOP Version 8).

Clinical Genomic Database (CGD)

Verheij syndromeAD

Manifestation: Cardiovascular; Craniofacial; Musculoskeletal; Ophthalmologic; Renal

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management

Comments: There is evidence that the condition may result from a deletion of multiple genes including PUF60 as well as heterozygous pathogenic variants in PUF60 alone

Refs: 19464398; 24140112

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PUF60 variants in ClinVar

13 Conditions Cataloged

not providedTotal: 172

8q24.3 microdeletion syndromeTotal: 102

not specifiedTotal: 54

Inborn genetic diseasesTotal: 45

PUF60-related disorderTotal: 38

Intellectual disability-cardiac anomalies-short stature-joint laxity syndromeTotal: 5

Intellectual disabilityTotal: 3

CHARGE syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_078480.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	48 clinvar		51
missense	3 clinvar	20 clinvar	110 clinvar	10 clinvar		143
nonsense	15 clinvar	11 clinvar	2 clinvar			28
start loss						0
frameshift	34 clinvar	28 clinvar	3 clinvar			65
splice donor/acceptor (+/-2bp)	3 clinvar	10 clinvar	8 clinvar			21
Total	55	69	126	58	0	308

Highest pathogenic variant AF is 0.0000027407848

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 104 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_078480.3	RefSeq	NP_510965.1	12	MANE Select
ENST00000526683.6	Ensembl	ENSP00000434359.1	12	MANE Select
NM_001136033.3	RefSeq	NP_001129505.1	10	Standard
NM_001271096.2	RefSeq	NP_001258025.1	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Spliceosome - Homo sapiens (human)
Metabolism of RNA
mRNA Splicing - Major Pathway
mRNA Splicing
Processing of Capped Intron-Containing Pre-mRNA

Biological Process

mRNA splicing, via spliceosome
apoptotic process

Molecular Function

DNA binding
RNA binding
protein binding
identical protein binding
cadherin binding

Cellular Component

nucleoplasm
cell junction

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000526683
Coding exons: 12
Length: 13516
Individuals with no LoFs: 124283
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 124288
p: 0.0000201

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.44	111	342	0.325	0.0000209	3605
Missense (PolyPhen)		8	63.955	0.12509		686
Synonymous	-2.28	180	145	1.24	0.0000103	1145
Loss of Function	4.33	2	25.7	0.0778	0.00000118	293

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000028	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: DNA- and RNA-binding protein, involved in several nuclear processes such as pre-mRNA splicing, apoptosis and transcription regulation. In association with FUBP1 regulates MYC transcription at the P2 promoter through the core-TFIIH basal transcription factor. Acts as a transcriptional repressor through the core-TFIIH basal transcription factor. Represses FUBP1-induced transcriptional activation but not basal transcription. Decreases ERCC3 helicase activity. Does not repress TFIIH-mediated transcription in xeroderma pigmentosum complementation group B (XPB) cells. Is also involved in pre-mRNA splicing. Promotes splicing of an intron with weak 3'-splice site and pyrimidine tract in a cooperative manner with U2AF2. Involved in apoptosis induction when overexpressed in HeLa cells. Isoform 6 failed to repress MYC transcription and inhibited FIR-induced apoptosis in colorectal cancer. Isoform 6 may contribute to tumor progression by enabling increased MYC expression and greater resistance to apoptosis in tumors than in normal cells. Modulates alternative splicing of several mRNAs. Binds to relaxed DNA of active promoter regions. Binds to the pyrimidine tract and 3'-splice site regions of pre-mRNA; binding is enhanced in presence of U2AF2. Binds to Y5 RNA in association with TROVE2. Binds to poly(U) RNA. {ECO:0000269|PubMed:10606266, ECO:0000269|PubMed:10882074, ECO:0000269|PubMed:11239393, ECO:0000269|PubMed:16452196, ECO:0000269|PubMed:16628215, ECO:0000269|PubMed:17579712}.;
Disease: DISEASE: Verheij syndrome (VRJS) [MIM:615583]: A syndrome characterized by growth retardation, delayed psychomotor development, dysmorphic facial features, and skeletal, mainly vertebral, abnormalities. Additional variable features may include coloboma, renal defects, and cardiac defects. {ECO:0000269|PubMed:24140112}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.142

Intolerance Scores

LoFtool: 0.357
RVIS EVS: -0.71
RVIS percentile EVS: 14.4

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.970

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium